Synthesis of 2-Vinylindole-3-Acetic Acid Derivatives via Cyanide

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Synthesis of 2‑Vinylindole-3-Acetic Acid Derivatives via CyanideCatalyzed Imino-Stetter Reaction Hong-Ahn Seo and Cheol-Hong Cheon* Department of Chemistry, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Republic of Korea S Supporting Information *

ABSTRACT: A new method for the synthesis of 2-vinylindole-3-acetic acid derivatives from aldimines, which are derived from 2-aminocinnamic acid derivatives and α,βunsaturated aldehydes, via a cyanide-catalyzed imino-Stetter reaction is described. Various types of 2-aminocinnamic acid derivatives and α,β-unsaturated aldehydes could be used in this protocol, and the desired 2-vinyl substituted indole-3-acetic acid derivatives were obtained in high yields. This cyanidecatalyzed imino-Stetter reaction was further extended to the preparation of indole-3-acetic acid derivatives bearing a carboxylic acid functionality at the 2-position, using aldimines obtained from glyoxylates and 2-aminocinnamic acid derivatives.

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INTRODUCTION The indole motif is found in a wide range of biologically active natural products, such as alkaloids and peptides, and is an important scaffold in the pharmaceutical industry. Hence, the development of new methods to access specific indole scaffolds has received significant attention from the synthetic and pharmaceutical communities.1 Among the numerous indole derivatives developed, 2-vinylindole-3-acetic acid derivatives 1 are particularly important because they are the key building blocks in the synthesis of several natural products2−5 such as flinderoles A−C2 and chartellines A−C.3 Therefore, the synthesis of indole derivatives 1 bearing various vinyl moieties at the 2-position is an important research topic, and several versatile synthetic routes to 1 have been developed.6−9 One of the conventional methods for the synthesis of 2vinylindole-3-acetic acid derivatives 1 involves the C-2 alkenylation of indole-3-acetic acid derivatives A via either direct C−H alkenylation bearing a suitable directing group on the nitrogen atom6 or a cross-coupling reaction of 2prefunctionalized indole-3-acetic acid with an appropriate vinyl counterpart7 (Scheme 1a). Moreover, the Fukuyama group developed an excellent method for the synthesis of these important compounds via the radical cyclization of isonitriles B derived from 2-aminocinnamic acid derivatives, followed by the Stille coupling of the resulting 2-stannylindoles C with alkynyl bromides (Scheme 1b).8,9 Despite the progress in the synthesis of 2-vinylindole-3-acetic acid derivatives 1, we strongly envisioned the need for the development of a new highefficiency protocol for the synthesis of these important compounds. Herein, we describe the development of a new method for the synthesis of 2-vinylindole-3-acetic acid derivatives 1 from aldimines 4, which in turn were obtained from 2-aminocinnamic acid derivatives 2 and α,β-unsaturated aldehydes 3 via © XXXX American Chemical Society

Scheme 1. Synthetic Routes to 2-Vinylindole-3-Acetic Acid Derivatives 1

the cyanide-catalyzed imino-Stetter reaction (Scheme 1c). Various 2-aminocinnamic acid derivatives 2 and α,β-unsaturated aldehydes 3 were applicable to this protocol, and the desired indole products 1 were obtained in excellent yields. Received: July 6, 2016

A

DOI: 10.1021/acs.joc.6b01621 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry Furthermore, this protocol was extended to nonvinyl conjugate aldehydes such as glyoxylates, affording the desired indoles.

compound with a catalytic amount of cyanide (Scheme 3). When 4aa was subjected to the previous optimal conditions10

RESULTS AND DISCUSSION Very recently, we developed a new protocol to access 2arylindole-3-acetic acid derivatives from aldimines, which were obtained from 2-aminocinnamic acid derivatives and aromatic aldehydes, in the presence of a catalytic amount of cyanide via a cyanide-catalyzed imino-Stetter reaction.10,11 Based on this result, we hypothesized that if a similar reaction mechanism was possible for aldimines 4, which were derived from 2aminocinnamic acid derivatives 2 and α,β-unsaturated aldehydes 3, then indole-3-acetic acid derivatives 1 bearing a vinyl moiety at the 2-position could be synthesized from 4 in the presence of a catalytic amount of cyanide. However, we expected a few challenges in the initial stages of the investigation (Scheme 2). The first and major concern was

Scheme 3. Initial Trials for the Synthesis of 2-Vinylindole-3Acetic Acid Derivative 4aa

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used for the synthesis of 2-arylindole-3-acetic acid derivatives, to our delight, the desired indole 1aa was obtained in 87% yield. Furthermore, the treatment of 4aa, which generated in situ by the condensation of 2a with 3a without further purification, with a catalytic amount of cyanide provided 1aa without any loss of efficiency. Since 1aa was obtained in a sufficiently high yield and with high reproducibility, we decided to use these conditions as the optimal reaction conditions for the synthesis of 2-vinylindole-3-acetic acid derivatives without any further optimization. Under these conditions, the generality of α,β-unsaturated aldehydes 3 was first investigated using ethyl 2-aminocinnamate 2a (Table 1). Various cinnamaldehyde derivatives participated in the reaction to afford the corresponding indoles 1 in high yields, regardless of the electronic and steric nature of the aryl group (entries 1−5). Furthermore, an α,β-unsaturated aldehyde bearing a heteroaromatic group was applied to this protocol,

Scheme 2. Expected Challenges in the Synthesis of 2Vinylindole-3-Acetic Acid Derivatives 1 from Aldimines 4 with Cyanide

the regioselectivity in the addition of cyanide to aldimines 4 (1,2- vs 1,4-addition). If cyanide undergoes 1,2-addition to 4, the resulting cyanide adducts 5 might undergo proton transfer to generate anions 6, which are the corresponding umpolung of aldimines 4. Subsequent imino-Stetter reaction via 5-exo-trig cyclization would afford the expected 2-vinylindole-3-acetic acid derivatives 1. On the other hand, 1,4-adducts 7 of cyanide to 4 could yield quinoline compounds 8 via 6-exo-trig cyclization. Another concern was the efficiency of the tautomerization of 1,2-adducts 5 to generate anionic intermediates 6. Regarding the regioselectivity, we expected that 1,2-addition of cyanide to 4 would be the major pathway leading to 5, since HCN addition of the aldimines of α,β-unsaturated aldehydes with an aniline derivative, i.e., the Strecker reaction of α,βunsaturated aldehydes, generally provided 1,2-adducts rather than 1,4-adducts.12 In addition, the efficiency of tautomerization of cyanide adducts 5 might depend on the relative stability between 1,2-adducts 5 and anionic 6. Because the pKa values of benzylic and allyllic protons are similar,13 we could anticipate that the stability of carbanions 6 generated from 5 via proton transfer might be similar to that in the case of the cyanide adducts of aldimines obtained from 2-aminocinnamic acid derivatives 2 and aromatic aldehydes. Thus, we expected that umpolung 6 could be generated from cyanide adducts 5 via tautomerization. With these considerations in mind, we tested our working hypothesis in the synthesis of 2-vinylindole-3-acetic acid derivatives using aldimine 4aa, which was derived from ethyl 2-aminocinnamate 2a and cinnamaldehyde 3a, as a model

Table 1. Substrate Scope of α,β-Unsaturated Aldehydes

a

entry

indole 1

R1

R′

R

yield (%)

1 2 3 4 5 6 7 8 9 10 11a 12a,b

1aa 1ab 1ac 1ad 1ae 1af 1ag 1ah 1ai 1aj 1ba 1ca

H H H H H H H H H H Br OMe

H H H H H H H H H Me H H

Ph 4-ClC6H4 4-BrC6H4 4-MeOC6H4 2-MeOC6H4 2-furyl H Me Et Ph Ph Ph

89 93 88 90 94 88 34 62 49 96 95 20

Methyl ester of 2-aminocinnamic acid was used. performed at 100 °C for 24 h.

B

b

Reaction was

DOI: 10.1021/acs.joc.6b01621 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry and the desired product 1af was obtained without any decrease in catalytic efficiency (entry 6). However, when the aldimines obtained from α,β-unsaturated aldehydes bearing an alkyl group at the β-position were subjected to the optimized conditions, the desired indoles 1 were obtained in only moderate yields, and hydrolysis of the aldimines competed with the indolization, leading to ethyl 2-aminocinnamate 2a (entries 7−9).14 An α,βdisubstituted α,β-unsaturated aldehyde was applicable to in this protocol, providing the desired indole 1aj in an excellent yield (entry 10). Finally, the effect of substituents at the 2aminocinnamate moiety on this transformation was investigated. The electronic nature of the substituent on the aryl group in 2-aminocinnamates 2 had a dramatic effect on this reaction (entries 1, 11, and 12). The reactions of 2aminocinnamate derivatives bearing electron-neutral and withdrawing groups provided the corresponding indoles in excellent yields (entries 1 and 11). On the other hand, the presence of an electron-donating substituent led to low yield of the indole product 1ca even at an elevated temperature (entry 12). The substrate scope of 2-aminocinnamic acid derivatives 2 was further explored in this transformation with cinnamaldehyde 3a (Table 2). First, the effect of the size of an alkyl group

To test the practicality of this protocol, this reaction was performed on a 20 mmol scale (Scheme 4). We found that this transformation could be performed without any decrease in efficiency. With these results in hand, we further investigated the utility of this protocol (Scheme 5). Since many indole monoterpene Scheme 5. Further Transformations of Indole 1da

Table 2. Substrate Scope of 2-Aminocinnamic Acid Derivatives

entry

indole 1

Y

yield (%)

1 2 3 4 5 6 7

1da 1aa 1ea 1fa 1ga 1ha 1ia

OMe OEt Oi-Pr Ot-Bu N(Et)2 N(CH2)5 N(Bn)Boc

98 89 98 85 88 74 88

alkaloids possess the structural scaffold of an indole-3-acetic acid derivative bearing an alkyl group at the 2-position,16 we first attempted to develop a synthetic route to 2-alkylindole-3acetic acid derivatives17 from 2-vinylindole-3-acetic acid derivatives. When 1da was subjected to palladium-catalyzed hydrogenation conditions, 2-alkylindole-3-acetic acid derivative 9 was obtained in a quantitative yield. In addition, we attempted to establish the diastereoselective construction of a pyrroloindole framework from the resulting vinylindoles 1 via a Brønsted acid-catalyzed [3 + 2]-cyclodimerization.18 Upon the treatment of 1da with a catalytic amount of trifluoroacetic acid (TFA), dimerization occurred to afford compound 10 in 60% yield. Next, the possibility of extending this protocol to other nonvinyl conjugate aldehydes such as glyoxylates and propargyl aldehydes was examined (Scheme 6). The structural motif Scheme 6. Extension to Other Conjugated Aldehydes

in the ester moiety of 2-aminocinnamate was examined. The size of the alkyl group in the ester moiety had little influence on this transformation, and the desired indoles 1 were obtained in excellent yields, regardless of the structure of the ester moiety (entries 1−4). Furthermore, several 2-aminocinnamides bearing different N-alkyl groups could be applied to this protocol, and the substituents on the nitrogen atom in the amide had negligible effect on the outcome of this reaction (entries 5− 7).15 Scheme 4. 20 mmol Scale Reaction

C

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materials, the reaction mixture was concentrated in vacuo to furnish the crude product of aldimine 4. Without further purification, 4 Å molecular sieves and sodium cyanide (0.10 mmol, 0.1 equiv) were added to a solution of 4 in DMF (10 mL) at room temperature. The mixture was stirred at 60 °C under an argon atmosphere until TLC analysis indicated the complete consumption of 4. Upon the complete consumption of 4, the reaction mixture was cooled to room temperature and filtered to remove the molecular sieves. The filtrate was concentrated in vacuo to provide the crude indole 1. The crude mixture was purified by column chromatography on silica to provide the desired indole 1. (E)-Ethyl 2-(2-Styryl-1H-indol-3-yl)acetate (1aa). Purification by column chromatography on silica (ethyl acetate/hexanes = 1:5) yielded a yellow solid (244 mg, 89%). Rf = 0.3 (ethyl acetate/hexanes = 1:4); mp 100−102 °C. 1H NMR (400 MHz, CDCl3, ppm) δ 8.23 (br, 1H), 7.61 (d, J = 7.8 Hz, 1H), 7.51 (d, J = 7.8 Hz, 2H), 7.37 (t, J = 7.4 Hz, 2H), 7.29 (t, J = 8.6 Hz, 2H), 7.25 (d, J = 16.4 Hz, 1H), 7.17− 7.21 (m, 1H), 7.11 (t, J = 7.4 Hz, 1H), 6.87 (d, J = 16.4 Hz, 1H), 4.15 (q, J = 7.2 Hz, 2H), 3.85 (s, 2H), 1.24 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3, ppm) δ 171.9, 137.1, 136.6, 133.9, 129.0, 129.0(2C), 128.0, 127.6, 126.6(2C), 123.5, 120.2, 119.2, 116.9, 110.9, 109.1, 61.2, 30.8, 14.5. HRMS (ESI) calcd for C20H19NNaO2 328.1308, found 328.1309. (E)-Ethyl 2-(2-(4-Chlorostyryl)-1H-indol-3-yl)acetate (1ab). Purification by column chromatography on silica (ethyl acetate/hexanes = 1:5) yielded a yellow solid (316 mg, 93%). Rf = 0.3 (ethyl acetate/ hexanes = 1:5); mp 144−145 °C. 1H NMR (400 MHz, CDCl3, ppm) δ 8.23 (br, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.40−7.43 (m, 2H), 7.28− 7.34 (m, 3H), 7.17−7.23 (m, 2H), 7.11 (t, J = 7.0 Hz, 1H), 6.80 (d, J = 16.4 Hz, 1H), 4.15 (q, J = 7.0 Hz, 2H), 3.85 (s, 2H), 1.24 (t, J = 7.0 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3, ppm) δ 172.0, 136.7, 135.6, 133.6, 133.4, 129.1(2C), 129.0, 127.7(2C), 126.1, 123.7, 120.3, 119.2, 117.4, 110.9, 109.3, 61.3, 30.8, 14.5. HRMS (ESI) calcd for C20H18ClNNaO2 362.0918, found 362.0919. (E)-Ethyl 2-(2-(4-Bromostyryl)-1H-indol-3-yl)acetate (1ac). Purification by column chromatography on silica (ethyl acetate/hexanes = 1:5) yielded a yellow solid (338 mg, 88%). Rf = 0.5 (ethyl acetate/ hexanes = 1:3); mp 146−148 °C. 1H NMR (400 MHz, CDCl3, ppm) δ 8.22 (br, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.48 (d, J = 8.6 Hz, 2H), 7.35 (d, J = 8.6 Hz, 2H), 7.29 (d, J = 7.8 Hz, 1H), 7.11 (t, J = 7.1 Hz, 2H), 7.09−7.14 (m, 1H), 6.78 (d, J = 16.4 Hz, 1H), 4.15 (q, J = 7.0 Hz, 2H), 3.86 (s, 2H), 1.24 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3, ppm) δ 172.1, 136.7, 136.1, 133.7, 132.0(2C), 128.9, 128.0(2C), 126.2, 123.7, 121.5, 120.3, 119.2, 117.4, 110.9, 109.3, 61.4, 30.8, 14.5. HRMS (ESI) calcd for C20H18BrNNaO2 406.0413, found 406.0415. (E)-Ethyl 2-(2-(4-Methoxystyryl)-1H-indol-3-yl)acetate (1ad). Purification by column chromatography on silica (ethyl acetate/hexanes = 1:5) yielded a yellow solid (302 mg, 90%). Rf = 0.3 (ethyl acetate/ hexanes = 1:5); mp 104−105 °C. 1H NMR (400 MHz, DMSO-d6, ppm) δ 11.21 (br, 1H), 7.53 (d, J = 8.2 Hz, 2H), 7.40 (d, J = 7.8 Hz, 1H), 7.29, (d, J = 7.8 Hz, 1H), 7.21 (d, J = 16.4 Hz, 1H), 7.05−7.15, (m, 2H), 6.96 (m, 3H), 4.04 (q, J = 7.0 Hz, 2H), 3.89 (s, 2H), 3.77 (s, 3H), 1.15 (t, J = 6.9 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3, ppm) δ 171.9, 159.7, 136.4, 134.2, 129.9, 129.2, 127.9(2C), 127.2, 123.2, 120.2, 119.1, 114.9, 114.5(2C), 110.7, 108.4, 61.1, 55.6, 30.8, 14.5. HRMS (ESI) calcd for C21H21NNaO3 358.1414, found 358.1413. (E)-Ethyl 2-(2-(2-Methoxystyryl)-1H-indol-3-yl)acetate (1ae). Purification by column chromatography on silica (ethyl acetate/hexanes = 1:3) yielded a yellow solid (315 mg, 94%). Rf = 0.3 (ethyl acetate/ hexanes = 1:3); mp 108−110 °C. 1H NMR (400 MHz, CDCl3, ppm) δ 8.48 (br, 1H), 7.54 (dd, J = 12.7, 7.6 Hz, 2H), 7.15−7.25 (m, 3H), 7.01−7.12 (m, 3H), 6.91 (t, J = 7.4 Hz, 1H), 6.82 (d, J = 8.2 Hz, 1H), 4.10 (q, J = 6.7 Hz, 2H), 3.80 (s, 2H), 3.77 (s, 3H), 1.16 (t, J = 6.9 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3, ppm) δ 172.2, 157.0, 136.7, 134.7, 129.1, 126.4, 126.1, 123.3, 122.1, 121.2, 120.1, 119.2, 117.2, 111.3, 111. 0, 108.6, 61.3, 55.7, 30.9, 14.5. HRMS (ESI) calcd for C21H21NNaO3 358.1414, found 358.1415. (E)-Ethyl 2-(2-(2-(Furan-2-yl)vinyl)-1H-indol-3-yl)acetate (1af). Purification by column chromatography on silica (ethyl acetate/

present in the conjugate aldehydes strongly affected the efficiency of this transformation. The reaction of aldimine 11 derived from ethyl glyoxylate with 2a provided the expected indole 12 in 63% yield, even under unoptimized conditions.19 However, this protocol could not be extended to aldimines derived from propargyl aldehydes. Disappointingly, when aldimine 13 was subjected to this protocol,20 the desired product 14 was not formed; instead, a complex mixture was obtained.

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CONCLUSIONS In conclusion, a new method for the synthesis of 2-vinyl substituted indole-3-acetic acid derivatives from aldimines, which were prepared using 2-aminocinnamic acid derivatives and α,β-unsaturated aldehydes, was developed via a cyanidecatalyzed imino-Stetter reaction. Various α,β-unsaturated aldehydes and 2-aminocinnamic acid derivatives were applicable to this protocol, and the desired 2-vinylindole-3-acetic acid derivatives were obtained in excellent yields. The synthetic utility of our method was demonstrated by converting the resulting indoles into various other compounds. This cyanidecatalyzed imino-Stetter reaction was further extended to the synthesis of indole-3-acetic acid derivatives bearing a carboxylic acid functionality at the 2-position, using aldimines obtained from glyoxylates and 2-aminocinnamic acid derivatives. Further studies on the application of the current method to the total synthesis of indole monoterpene alkaloids and the extension of cyanide-catalyzed imino-Stetter reaction to other N-containing heterocyclic compounds are underway in our laboratory.

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EXPERIMENTAL SECTION

General. All reactions were carried out in oven-dried glassware under an argon atmosphere, unless otherwise noted. Except as otherwise indicated, all reactions were magnetically stirred and monitored by analytical thin-layer chromatography (TLC) using precoated silica gel glass plates (0.25 mm) with F254 indicator. Visualization was accomplished by UV light (254 nm), with a combination of potassium permanganate and/or phosphomolybdic acid solution as an indicator. Flash column chromatography was performed using silica gel 60 (230−400 mesh). Yields refer to chromatographically and spectroscopically pure compounds, unless otherwise noted. Commercial grade reagents and solvents were used without further purification. 2-Aminocinnamic acid derivatives 2 were prepared from 2-nitrocinnamic acid by the literature procedure.10 2Nitrocinnamic acid and all α,β-unsaturated aldehydes were purchased from commercial suppliers and used without further purification unless otherwise noted. 1H NMR and 13C NMR spectra were recorded at 400/500 and 100/125 MHz spectrometers, respectively. Tetramethylsilane (δ: 0.0 ppm) and a residual NMR solvent (either CDCl3 (δc: 77.16 ppm) or DMSO (δC: 39.52 ppm) were used as internal standards for 1H NMR and 13C NMR spectra, respectively. The proton spectra are reported as follows: δ (position of proton, multiplicity, coupling constant J, number of protons). Multiplicities are indicated by s (singlet), d (doublet), t (triplet), q (quartet), p (quintet), h (septet), m (multiplet) and br (broad). High-resolution mass spectra (HRMS) were recorded on a quadrupole time-of-flight mass spectrometer (QTOF-MS) in electrospray ionization (ESI) mode as ionization method. General Procedure for the Synthesis of 2-Vinylindole-3acetic acid Derivatives (Tables 1 and 2). To a 50 mL roundbottom flask were added (E)-2-aminocinnamic acid derivative 2 (1.0 mmol), Na2SO4 (330 mg), and MgSO4 (330 mg), and the reaction mixture was dissolved in THF (10 mL). To the above solution was added an α,β-unsaturated aldehyde 3 (1.0 mmol). The mixture was stirred at room temperature and monitored by 1H NMR analysis of the crude mixture. After the complete consumption of the starting D

DOI: 10.1021/acs.joc.6b01621 J. Org. Chem. XXXX, XXX, XXX−XXX

Article

The Journal of Organic Chemistry

Hz, 2H), 7.29 (d, J = 7.4 Hz, 1H), 7.23 (d, J = 1.6 Hz, 1H), 7.20 (d, J = 5.5 Hz, 1H), 7.02−7.05 (m, 1H), 6.84−6.90 (m, 2H), 3.87 (s, 3H), 3.84 (s, 2H), 3.69 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3, ppm) δ 172.1, 154.4, 136.9, 134.4, 131.5, 129.2, 128.8, 127.8, 127.2, 126.4, 116.6, 113.5, 111.4, 108.5, 100.7, 55.9, 52.1, 30.4. HRMS (ESI) calcd for C20H19NNaO3 344.1257, found 344.1259. (E)-Methyl 2-(2-Styryl-1H-indol-3-yl)acetate (1da). Purification by column chromatography on silica (ethyl acetate/hexanes = 1:6) yielded a yellow solid (285 mg, 98%). Rf = 0.6 (ethyl acetate/hexanes = 1:3); mp 104−105 °C. 1H NMR (400 MHz, CDCl3, ppm) δ 8.27 (br, 1H), 7.58 (d, J = 7.8 Hz, 1H), 7.47 (d, J = 7.4 Hz, 2 H), 7.35 (t, J = 7.4 Hz, 2H), 7.22−7.28 (m, 2H), 7.15−7.21 (m, 2H), 7.10 (t, J = 7.4 Hz, 1H), 6.82 (d, J = 16.4 Hz, 1H), 3.85 (s, 2H), 3.68 (s, 3H). 13 C{1H} NMR (100 MHz, CDCl3, ppm) δ 172.4, 137.1, 136.6, 133.9, 129.0(2C), 128.1, 127.7, 126.6(2C), 123.6, 120.3, 119.2, 116.8, 110.9, 108.9, 52.4, 30.5. HRMS (ESI) calcd for C19H17NNaO2 314.1151, found 314.1152. (E)-Isopropyl 2-(2-Styryl-1H-indol-3-yl)acetate (1ea). Purification by column chromatography on silica (ethyl acetate/hexanes = 1:6) yielded a yellow solid (313 mg, 98%), Rf = 0.6 (ethyl acetate/hexanes = 1:3); mp 96−98 °C. 1H NMR (400 MHz, CDCl3, ppm) δ 8.23 (br, 1H), 7.61 (d, J = 7.8 Hz, 1H), 7.51 (d, J = 7.4 Hz, 2H), 7.37 (t, J = 7.6 Hz, 2H), 7.30 (t, J = 8.6 Hz, 2H), 7.25 (d, J = 16.4 Hz, 1H), 7.20 (t, J = 7.4 Hz, 1H), 7.11 (t, J = 7.4 Hz, 1H), 6.87 (d, J = 16.4 Hz, 1H), 4.96−5.06 (m, 1H), 3.82 (s, 2H), 1.21 (d, J = 6.3 Hz, 6H). 13C{1H} NMR (100 MHz, CDCl3, ppm) δ 171.6, 137.2, 136.6, 133.9, 129.0, 129.0(2C), 127.9, 127.5, 126.6(2C), 123.4, 120.1, 119.2, 117.0, 110.9, 109.1, 68.7, 31.2, 22.1(2C). HRMS (ESI) calcd for C21H21NNaO2 342.1464, found 342.1468. (E)-tert-Butyl 2-(2-Styryl-1H-indol-3-yl)acetate (1fa). Purification by column chromatography on silica (ethyl acetate/hexanes = 1:5) yielded a brown solid (284 mg, 85%). Rf = 0.3 (ethyl acetate/hexanes = 1:5); mp 124−125 °C. 1H NMR (400 MHz, CDCl3, ppm) δ 8.20 (br, 1H), 7.61 (d, J = 7.8 Hz, 1H), 7.52 (d, J = 7.4 Hz, 2H), 7.37 (t, J = 7.6 Hz, 2H), 7.27−7.33 (m, 2H), 7.17−7.24 (m, 2H), 7.11 (t, J = 7.4 Hz, 1H), 6.88 (d, J = 16.4 Hz, 1H), 3.77 (s, 2H), 1.42 (s, 9H). 13 C{1H} NMR (100 MHz, CDCl3, ppm) δ 171.1, 137.2, 136.6, 133.7, 129.1, 129.0(2C), 127.9, 127.2, 126.6(2C), 123.4, 120.1, 119.4, 117.1, 110.7, 109.8, 81.1, 32.2, 28.3(3C). HRMS (ESI) calcd for C22H23NNaO2 356.1621, found 356.1621. (E)-N,N-Diethyl-2-(2-styryl-1H-indol-3-yl)acetamide (1ga). Purification by column chromatography on silica (ethyl acetate/hexanes = 1:3) yielded a yellow solid (293 mg, 88%). Rf = 0.3 (ethyl acetate/ hexanes = 1:3); mp 151−152 °C. 1H NMR (400 MHz, CDCl3, ppm) δ 8.49 (br, 1H), 7.59 (d, J = 7.8 Hz, 1H), 7.47 (d, J = 7.4 Hz, 2H), 7.34 (t, J = 7.4 Hz, 2H), 7.21−7.30 (m, 3H), 7.15 (t, J = 7.4 Hz, 1H), 7.07 (t, J = 7.1 Hz, 1H), 6.83 (d, J = 16.4 Hz, 1H), 3.91 (s, 2H), 3.39 (q, J = 7.0 Hz, 2H), 3.32 (q, J = 7.0 Hz, 2H), 1.09 (t, J = 7.0 Hz, 3H), 1.02 (t, J = 7.0 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3, ppm) δ 170.8, 137.3, 136.8, 133.7, 128.9, 128.8, 127.8, 127.3, 126.6, 123.3, 120.0, 119.0, 117.1, 110.9, 109.8, 42.6, 40.8, 31.4, 14.3, 13.3. HRMS (ESI) calcd for C22H24N2NaO 355.1781, found 355.1782. (E)-1-(Piperidin-1-yl)-2-(2-styryl-1H-indol-3-yl)ethanone (1ha). The spectroscopic data were in good agreement with the literature.11 Purification by column chromatography on silica (ethyl acetate/ hexanes = 1:3) yielded a yellow solid (255 mg, 74%). Rf = 0.2 (ethyl acetate/hexanes = 1:3). 1H NMR (400 MHz, CDCl3, ppm) δ 8.27 (br, 1H), 7.61 (d, J = 7.8 Hz, 1H), 7.51 (d, J = 7.4 Hz, 2H), 7.28−7.40 (m, 5H), 7.20 (t, J = 7.4 Hz, 1H), 7.10 (t, J = 7.4 Hz, 1H), 3.94 (s, 2H), 3.55−3.61 (m, 2H), 3.34−3.41 (m, 2H), 1.41−1.54 (m, 4H), 1.18− 1.25 (m, 2H). 13C{1H} NMR (100 MHz, CDCl3, ppm) δ 169.8, 137.2, 136.7, 133.4, 129.0(2C), 128.6, 127.9, 127.3, 126.6(2C), 123.4, 120.1, 119.2, 117.1, 110.8, 109.9, 47.5, 43.4, 31.5, 26.2, 25.8, 24.6. HRMS (ESI) calcd for C23H24N2NaO 367.1781, found 367.1780. (E)-N-Benzyl-N-(tert-butyoxycarbonyl)-2-(2-styryl-1H-indol-3-yl)acetamide (1ia). Purification by column chromatography on silica (ethyl acetate/hexanes = 1:5) yielded a brown solid (411 mg, 88%). Rf = 0.3 (ethyl acetate/hexanes = 1:5); mp 144−145 °C. 1H NMR (400 MHz, CDCl3, ppm) δ 8.21 (br, 1H) 7.45−7.51 (m, 3H) 7.34 (t, J = 7.4 Hz, 2H) 7.20−7.29 (m, 8H) 7.16 (t, J = 7.6 Hz, 1H) 7.05 (t, J =

hexanes = 1:5) afforded a yellow solid (260 mg, 88%). Rf = 0.4 (ethyl acetate/hexanes = 1:3); mp 145−146 °C. 1H NMR (400 MHz, CDCl3, ppm) δ 8.14 (br, 1H), 7.58 (d, J = 7.8 Hz, 1H), 7.41 (s, 1H), 7.27 (d, J = 7.0 Hz, 1H), 7.17 (t, J = 7.6 Hz, 1H), 7.07−7.15 (m, 2H), 6.65 (d, J = 16.4 Hz, 1H), 6.41−6.45 (m, 1H), 6.35 (d, J = 3.1 Hz, 1H), 4.15 (q, J = 7.0 Hz, 2H), 3.84 (s, 2H), 1.24 (t, J = 7.0 Hz, 3H). 13 C{1H} NMR (100 MHz, CDCl3, ppm) δ 171.7, 153.0, 142.6, 136.6, 133.6, 129.1, 123.6, 120.3, 119.3, 115.3, 115.3, 112.0, 110.7, 109.4, 109.1, 61.1, 30.7, 14.4. HRMS (ESI) calcd for C18H17NNaO3 318.1101, found 318.1101. Ethyl 2-(2-Vinyl-1H-indol-3-yl)acetate (1ag). Purification by column chromatography on silica (ethyl acetate/hexanes = 1:5) yielded yellow liquid (78 mg, 34%). Rf = 0.5 (ethyl acetate/hexanes = 1:3). 1H NMR (400 MHz, CDCl3, ppm) δ 8.15 (br, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.30 (d, J = 7.8 Hz, 1H), 7.19 (t, J = 7.2 Hz, 1H), 7.10 (t, J = 7. 0 Hz, 1H), 6.88 (dd, J = 17.8, 11.2 Hz, 1H), 5.53 (d, J = 18. 0 Hz, 1H), 5.32 (d, J = 11.0 Hz, 1H), 4.13 (q, J = 7.2 Hz, 2H), 3.78 (s, 2H), 1.23 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3, ppm) δ 171.9, 136.2, 133.7, 128.8, 125.5, 123.4, 120.1, 119.4, 112.7, 110.9, 108.3, 61.1, 30.6, 14.4. HRMS (ESI) calcd for C14H15NNaO2 252.0995, found 252.0996. (E)-Ethyl 2-(2-(Prop-1-en-1-yl)-1H-indol-3-yl)acetate (1ah). Purification by column chromatography on silica (ethyl acetate/hexanes = 1:8) yielded a yellow solid (151 mg, 62%). Rf = 0.5 (ethyl acetate/ hexanes = 1:5); mp 81−86 °C. Existed as an inseparable mixture of (E)- and (Z)-isomers (E/Z = 10:1). 1H NMR (400 MHz, CDCl3, ppm) δ 8.23 (br, 1H), 7.53 (d, J = 7.4 Hz, 1H), 7.03−7.14 (m, 3H), 6.43 (d, J = 15.7 Hz, 1H), 5.83−5.93 (m, 1H), 4.11 (q, J = 7.0 Hz, 2H), 3.73 (s, 2H), 1.80 (d, J = 6.7 Hz, 3H), 1.20 (t, J = 7.0 Hz, 3H). 13 C{1H} NMR (100 MHz, CDCl3, ppm) δ 172.4, 136.2, 134.2, 129.0, 125.6, 122.6, 122.6, 120.0, 119.9, 118.9, 110.9, 105.9, 61.2, 30.7, 19.0, 14.5. HRMS (ESI) calcd for C15H17NNaO2 266.1151, found 266.1150. (E)-Ethyl 2-(2-(but-1-en-1-yl)-1H-indol-3-yl)acetate (1ai). Purification by column chromatography on silica (ethyl acetate/hexanes = 1:6) yielded a yellow solid (127 mg, 49%). Rf = 0.6 (ethyl acetate/ hexanes = 1:3); mp 77−78 °C. 1H NMR (400 MHz, CDCl3, ppm) δ 8.04 (br, 1H), 7.56 (d, J = 7.8 Hz, 1H), 7.28 (d, J = 7.4 Hz, 1H), 7.15 (t, J = 7.4 Hz, 1H), 7.08 (t, J = 7.4 Hz, 1H), 6.54 (d, J = 16.0 Hz, 1H), 6.08 (dt, J = 15.9, 6.5 Hz, 1H), 4.13 (q, J = 7.0 Hz, 2H), 3.75 (s, 2H), 2.25−2.34 (m, 2H), 1.23 (t, J = 7.0 Hz, 3H), 1.12 (t, J = 7.4 Hz, 3H). 13 C{1H} NMR (100 MHz, CDCl3, ppm) δ 172.5, 136.3, 134.2, 132.5, 129.0, 122.7, 119.9, 118.9, 117.9, 110.9, 106.2, 61.2, 30.8, 26.6, 14.5, 13.9. HRMS (ESI) calcd for C16H19NNaO2 280.1313, found 280.1307. (E)-Ethyl 2-(2-(1-Phenylprop-1-en-2-yl)-1H-indol-3-yl)acetate (1aj). Purification by column chromatography on silica (ethyl acetate/hexanes = 1:3) yielded brown liquid (306 mg, 96%). Rf = 0.3 (ethyl acetate/hexanes = 1:3). 1H NMR (400 MHz, CDCl3, ppm) δ 8.05 (br, 1H), 7.64 (d, J = 7.8 Hz, 1H), 7.40 (d, J = 4.7 Hz, 3H), 7.33 (d, J = 7.8 Hz, 1H), 7.26−7.31 (m, 1H), 7.11−7.22 (m, 3H), 6.97 (s, 1H), 4.16 (q, J = 7.3 Hz, 2H), 3.89 (s, 2H), 2.33 (s, 3H), 1.25 (t, J = 7.0 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3, ppm) δ 172.5, 139.5, 137.6, 135.5, 131.4, 129.5, 129.2, 128.6, 128.6, 127.2, 122.7, 120.1, 119.3, 111.0, 105.8, 61.1, 31.8, 18.3, 14.5. HRMS (ESI) calcd for C21H21NNaO2 342.1464, found 342.1463. (E)-Methyl 2-(5-Bromo-2-styryl-1H-indol-3-yl)acetate (1ba). Purification by column chromatography on silica (ethyl acetate/hexanes = 1:5) yielded a yellow solid (352 mg, 95%). Rf = 0.3 (ethyl acetate/ hexanes = 1:5); mp 149−150 °C. 1H NMR (400 MHz, CDCl3, ppm) δ 8.29 (br, 1H), 7.69 (s, 1H), 7.49 (d, J = 7.4 Hz, 2H), 7.37 (t, J = 7.6 Hz, 2H), 7.30 (d, J = 7.4 Hz, 1H), 7.24−7.27 (m, 1H), 7.13−7.19 (m, 2H), 6.88 (d, J = 16.4 Hz, 1H), 3.81 (s, 2H), 3.71 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3, ppm) δ 172.0, 136.7, 135.1, 135.1, 130.7, 129.0 (2C), 128.7, 128.3, 126.7(2C), 126.3, 121.6, 116.3, 113.5, 112.2, 108.2, 52.5, 30.3. HRMS (ESI) calcd for C19H16BrNNaO2 392.0257, found 392.0260. (E)-Methyl 2-(5-Methoxy-2-styryl-1H-indol-3-yl)acetate (1ca). Purification by column chromatography on silica (ethyl acetate/ hexanes = 1:5) yielded a brown solid (64 mg, 20%). Rf = 0.4 (ethyl acetate/hexanes = 1:3); mp 142−144 °C. 1H NMR (400 MHz, CDCl3, ppm) δ 8.12 (br, 1H), 7.52 (d, J = 7.4 Hz, 2H), 7.38 (t, J = 7.4 E

DOI: 10.1021/acs.joc.6b01621 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry 7.5 Hz, 1H) 6.80 (d, J = 16.3 Hz, 1H) 4.88 (s, 2H) 4.53 (s, 2H) 1.39 (d, J = 1.4 Hz, 9H). 13C{1H} NMR (100 MHz, CDCl3, ppm) δ 174.3, 153.4, 138.2, 137.1, 136.5, 133.9, 129.2, 128.7, 128.3, 127.7, 127.6, 127.1, 126.8, 126.4, 123.2, 119.9, 119.4, 117.4, 110.5, 110.2, 83.4, 47.9, 33.7, 27.9. HRMS (ESI) calcd for C30H30N2NaO3 489.2149, found 489.2147. Ethyl 3-(2-Ethoxy-2-oxoethyl)-1H-indole-2-carboxylate (12). The spectroscopic data were in good agreement with the literature.19 Purification by column chromatography on silica (ethyl acetate/ hexanes = 1:5) yielded a yellow solid (173 mg, 63%). Rf = 0.5 (ethyl acetate/hexanes = 1:3). 1H NMR (400 MHz, CDCl3, ppm) δ 8.85 (br, 1H), 7.66 (d, J = 8.2 Hz, 1H), 7.37−7.42 (m, 1H), 7.33 (t, J = 7.4 Hz, 1H), 7.17 (t, J = 7.4 Hz, 1H), 4.41 (q, J = 7.0 Hz, 2H), 4.13−4.20 (m, 4H), 1.41 (t, J = 7.0 Hz, 3H), 1.25 (t, J = 7.0 Hz, 3H). HRMS (ESI) calcd for C15H17NNaO4 298.1050, found 298.1048. Methyl 2-(2-Phenethyl-1H-indol-3-yl)acetate (9). Purification by column chromatography on silica (ethyl acetate/hexanes = 1:6) yielded yellow liquid (276 mg, 94%). Rf = 0.6 (ethyl acetate/hexanes = 1:3). 1H NMR (400 MHz, CDCl3, ppm) δ 7.73 (br, 1H), 7.51−7.56 (m, 1H), 7.07−7.28 (m, 8H), 3.63 (s, 3H), 3.60 (s, 2H), 2.98−3.03 (m, 2H), 2.89−2.94 (m, 2H). 13C{1H} NMR (100 MHz, CDCl3, ppm) δ 172.8, 141.3, 136.4, 135.4, 128.8, (2C) 128.7, (2C) 128.5, 126.6, 121.7, 119.8, 118.6, 110.7, 104.8, 52.2, 36.2, 30.4, 28.5. HRMS (ESI) calcd for C19H19NNaO2 316.1308, found 316.1310. Compound (10). Purification by column chromatography on silica (ethyl acetate/hexanes = 1:5) yielded a yellow solid (175 mg, 60%). Rf = 0.5 (ethyl acetate/hexanes = 1:3); mp 208−210 °C. 1H NMR (500 MHz, CDCl3, ppm) δ 7.62 (d, J = 8.1 Hz, 1H), 7.52 (d, J = 7.6 Hz, 1H), 7.26−7.29 (m, 2H), 7.18−7.24 (m, 3H), 7.07−7.16 (m, 9H), 6.91−6.95 (m, 1H), 6.69 (d, J = 8.1 Hz, 1H), 5.53 (d, J = 7.3 Hz, 1H), 4.03−4.07 (m, 1H), 3.74−3.84 (m, 3H), 3.73 (s, 3H), 3.47 (s, 3H), 3.38−3.43 (m, 2H), 3.20 (d, J = 15.9 Hz, 1H), 3.13 (dd, J = 14.1, 5.9 Hz, 1H). 13C{1H} NMR (125 MHz, CDCl3, ppm) δ 172.3, 171.5, 144.2, 140.8, 138.3, 135.7, 133.3, 133.3, 132.8, 130.0, 128.9, 128.6, 128.0, 127.8, 127.4, 126.9, 122.5, 121.4, 120.2, 119.9, 118.9, 118.7, 111.2, 110.5, 106.7, 99.8, 61.3, 60.9, 52.0, 51.8, 46.5, 38.1, 30.4, 29.6. HRMS (ESI) calcd for C38H34N2NaO4 605.2411, found 605.2413.

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L.; Hierso, J.-C. Chem. Soc. Rev. 2012, 41, 3929. (e) Taber, D. F.; Tirunahari, P. K. Tetrahedron 2011, 67, 7195. (f) Vincente, R. Org. Biomol. Chem. 2011, 9, 6469. (g) Cacchi, S.; Fabrizi, G. Chem. Rev. 2011, 111, PR215. (h) Cacchi, S.; Fabrizi, G.; Goggiamani, A. Org. Biomol. Chem. 2011, 9, 641. (2) For the total synthesis of flinderoles, see: (a) Dethe, D. H.; Erande, R. D.; Ranjan, A. J. Org. Chem. 2013, 78, 10106. (b) Vallakati, R.; May, J. A. J. Am. Chem. Soc. 2012, 134, 6936. (c) Dethe, D. H.; Erande, R. D.; Ranjan, A. J. Am. Chem. Soc. 2011, 133, 2864. (d) Zeldin, R. M.; Toste, F. D. Chem. Sci. 2011, 2, 1706. (3) For the synthetic studies on chartellines A−C using 2vinylindole-3-acetic acid derivatives as the key intermediates, see: Kajii, S.; Nishikawa, T.; Isobe, M. Chem. Commun. 2008, 3121. (4) For other applications of 2-vinylindole-3-acetic acid derivatives as the key intermediates in the total synthesis of natural products, see: (a) Schultz, E. E.; Pujanauski, B. G.; Sarpong, R. Org. Lett. 2012, 14, 648. (b) Jones, S. B.; Simmons, B.; Mastracchio, A.; MacMillan, D. W. C. Nature 2011, 475, 183. (5) For the importance of 3-substituted 2-vinylindoles in organic synthesis, see: (a) Bara, K.; Schneider, C. Chem. - Eur. J. 2016, 22, 7074. (b) Zhao, J.-J.; Tang, M.; Zhang, H.-H.; Xu, M.-M.; Shi, F. Chem. Commun. 2016, 52, 5953. (c) Dai, W.; Jiang, X.-L.; Tao, J.-Y.; Shi, F. J. Org. Chem. 2016, 81, 185. (d) Wang, Y.; Sun, M.; Yin, L.; Shi, F. Adv. Synth. Catal. 2015, 357, 4031. (e) Zhao, J.-J.; Sun, S.-B.; He, S.H.; Wu, Q.; Shi, F. Angew. Chem., Int. Ed. 2015, 54, 5460. (f) Tan, W.; Li, X.; Gong, Y.-X.; Ge, M.-D.; Shi, F. Chem. Commun. 2014, 50, 15901. (6) For examples of C−H alkenylation at the C-2 position of indoles via C−H functionalization, see: (a) Sharma, S.; Han, S.; Kim, M.; Mishra, N. L.; Park, J.; Shin, Y.; Ha, J.; Kwak, J. H.; Jung, Y. H.; Kim, I. S. Org. Biomol. Chem. 2014, 12, 1703. (b) Lanke, V.; Prabhu, K. R. Org. Lett. 2013, 15, 2818. (c) García-Rubia, A.; Arrayás, R. G.; Carretero, J. C. Angew. Chem., Int. Ed. 2009, 48, 6511. (d) Grimster, N. P.; Gauntlett, C.; Godfrey, C. R. A.; Gaunt, M. J. Angew. Chem., Int. Ed. 2005, 44, 3125. (7) For examples of alkenylation at the C-2 position of C-2 prefunctionalized indoles, see: (a) Teichert, J. F.; Fañanás-Mastral, M.; Feringa, B. L. Synthesis 2012, 44, 409. (b) Sydorenko, N.; Zificsak, C. A.; Gerasyuto, A. I.; Hsung, R. P. Org. Biomol. Chem. 2005, 3, 2140. (c) Molander, G. A.; Felix, L. A. J. Org. Chem. 2005, 70, 3950. (8) (a) Tokuyama, H.; Kaburagi, Y.; Fukuyama, T. Synthesis 2000, 2000, 429. (b) Fukuyama, T.; Chen, X.; Peng, G. J. Am. Chem. Soc. 1994, 116, 3127. (9) Tobisu, M.; Fujihara, H.; Koh, K.; Chatani, N. J. Org. Chem. 2010, 75, 4841. (10) Lee, S. J.; Seo, H.-A.; Cheon, C.-H. Adv. Synth. Catal. 2016, 358, 1566. (11) Prior to our report, a similar transformation was reported from an aldimine in a two-step protocol: the formation of Strecker product followed by the treatment of the resulting Strecker product with a stoichiometric amount of a strong base, leading to umpolung of aldimine. Subsequently, the resulting umpolung underwent 5-exo-trig cyclization, providing indole-3-acetic acid derivative, see: Opatz, T.; Ferenc, D. Org. Lett. 2006, 8, 4473. (12) (a) Nasreen, A. Tetrahedron Lett. 2013, 54, 3797. (b) Chaturvedi, D.; Chaturvedi, A. K. P.; Dwivedi, K.; Mishra, N. Synlett 2013, 24, 33. (c) Pathare, S. P.; Akamanchi, K. G. Tetrahedron Lett. 2012, 53, 871. (13) For the pKa values of allylic and benzylic protons, see: http:// www.chem.wisc.edu/areas/reich/pkatable/index.htm. (14) Indole-3-acetic acid derivatives 1ag−1ai bearing β-alkylvinyl groups were not very stable and decomposed during the storage even at 0 °C. However, they were significantly stable during purification through conventional separation methods. (15) The poor solubility of compound 1ha decreased its yield compared to other indoles. The piperidine moiety in the amide in 1ha significantly decreased the solubility, leading to loss of yield during the separation of 1ha.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.6b01621. 1 H NMR and 13C{1H} NMR spectra for compounds 1, 9, 10, 12 (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Phone: +82-2-3290-3147. Fax: +82-2-3290-3121. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by National Research Foundation of Korea (NRF) grants funded by the Korean Government (NRF2015R1D1A1A01057200, NRF-2015M2A8A4021635, and NRF-20100020209). C.-H.C. thanks the financial support from an NRF grant funded by the Korean Government (NRF-2014-011165, Center for New Directions in Organic Synthesis).

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REFERENCES

(1) For reviews on the synthesis of indole derivatives, see: (a) Guo, T.; Huang, F.; Yu, L.; Yu, Z. Tetrahedron Lett. 2015, 56, 296. (b) Wu, H.; He, Y.-P.; Shi, F. Synthesis 2015, 47, 1990. (c) Inman, M.; Moody, C. J. Chem. Sci. 2013, 4, 29. (d) Platon, M.; Amardeil, R.; Djakovitch, F

DOI: 10.1021/acs.joc.6b01621 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry (16) For reviews on monoterpene indole alkaloids, see: (a) O’Connor, S. E.; Maresh, J. J. Nat. Prod. Rep. 2006, 23, 532. (b) Saxton, J. E. Nat. Prod. Rep. 1997, 14, 559. (17) 2-Alkylindole-3-acetic acid derivatives 9 were generally synthesized via the alkylation of indole-3-acetic acid derivatives at the C-2 position. For examples, see: (a) Bennasar, M. L.; Solé, D.; Roca, T.; Valldosera, M. Tetrahedron 2015, 71, 2246. (b) Jain, H. D.; Zhang, C.; Zhou, S.; Zhou, H.; Ma, J.; Liu, X.; Liao, X.; Deveau, A. M.; Dieckhaus, C. M.; Johnson, M. A.; Smith, K. S.; Macdonald, T. L.; Kakeya, H.; Osada, H.; Cook, J. M. Bioorg. Med. Chem. 2008, 16, 4626. (18) Yin, L.; Wang, Y.; Sun, M.; Shi, F. Adv. Synth. Catal. 2016, 358, 1093. (19) For the previous synthesis of compound 12, see: Yasui, E.; Wada, M.; Takamura, N. Tetrahedron 2009, 65, 461. (20) Conventionally, 2-alkynylindole-3-acetic acid derivatives 14 are prepared by the Sonogashira coupling of indole-3-acetic acid derivatives bearing a halide at the 2-position with a terminal alkyne. For recent examples, see: (a) Hsu, S. W.; Cheng, H. Y.; Huang, A. C.; Ho, T. L.; Hou, D. R. Eur. J. Org. Chem. 2014, 2014, 3109. (b) Ji, D.M.; Xu, M.-H. Chem. Commun. 2010, 46, 1550. (c) See also ref 3.

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DOI: 10.1021/acs.joc.6b01621 J. Org. Chem. XXXX, XXX, XXX−XXX